title: Functionalization of polyanhydride microparticles with di-mannose influences uptake by and intracellular fate within dendritic cells.
abstract: Innovative vaccine delivery platforms can facilitate the development of effective single-dose treatment regimens to control emerging and re-emerging infectious diseases. Polyanhydride microparticles are promising vaccine delivery vehicles due to their ability to stably maintain antigens, provide tailored release kinetics and function as adjuvants. A major obstacle for the use of microparticle-based vaccines, however, is their limited uptake by dendritic cells (DCs). In this study, we functionalized the microparticle surface with di-mannose in order to target C-type lectin receptors (CLRs) on DCs. Polyanhydride particles based on sebacic acid (SA), 1,6-bis(p-carboxyphenoxy)hexane (CPH) and 1,8-bis(p-carboxyphenoxy)-3,6-dioxaoctane (CPTEG) were evaluated. Co-incubation of di-mannose-functionalized microparticles up-regulated the expression of CLRs on DCs. More importantly, di-mannose functionalization increased the uptake, as measured by the percentage of cells internalizing particles. The uptake of CPH:SA microparticles increased ∼20-fold, from 0.82% (non-functionalized) to 20.2%, and internalization of CPTEG:CPH microparticles increased ∼7-fold from 1.35% (non-functionalized) to 9.3% upon di-mannose functionalization. Both di-mannose-functionalized and non-functionalized particles trafficked to lysosomes. Together, these studies demonstrate that employing rational vaccine design principles, such as the targeting of CLRs on antigen-presenting cells, can enhance delivery of encapsulated antigens and potentially induce a more robust adaptive immune response.
authors.affiliation: Department of Veterinary Microbiology and Preventive Medicine, Iowa State University, Ames, IA 50011, USA.
authors.forename: Yashdeep
authors.initials: Y
authors.lastname: Phanse
authors.forename: Brenda R
authors.initials: BR
authors.lastname: Carrillo-Conde
authors.forename: Amanda E
authors.initials: AE
authors.lastname: Ramer-Tait
authors.forename: Rajarshi
authors.initials: R
authors.lastname: Roychoudhury
authors.forename: Nicola L B
authors.initials: NL
authors.lastname: Pohl
authors.forename: Balaji
authors.initials: B
authors.lastname: Narasimhan
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wannemuehler
authors.forename: Bryan H
authors.initials: BH
authors.lastname: Bellaire
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000166:cytology* / Q000378:metabolism*; D004187:Disaccharides / Q000737:chemistry*; D004705:Endocytosis; D042541:Intracellular Space / Q000378:metabolism*; D037181:Lectins, C-Type / Q000172:deficiency / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008358:Mannose / Q000737:chemistry*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000172:deficiency / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008863:Microspheres; D056951:Photoelectron Spectroscopy; D049388:Polyanhydrides / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000378:metabolism
chemical_list: D004187:Disaccharides; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D049388:Polyanhydrides; D011108:Polymers; D011956:Receptors, Cell Surface; D008358:Mannose
keywords: C-type lectin receptors; Di-mannose; Microparticles; Polyanhydride; Targeted vaccines; Uptake